HK1052512B

HK1052512B - Method for the preparation of citalopram

Info

Publication number: HK1052512B
Application number: HK03104874.0A
Authority: HK
Inventors: Petersen Hans; Harold Rock Michael
Original assignee: H. 隆德贝克有限公司
Priority date: 1999-12-30
Filing date: 1999-12-30
Publication date: 2006-03-03
Also published as: US20060079700A1; US20020198391A1; EP1246813A1; KR100653141B1; SK11052002A3; NO20023150L; WO2001049672A1; MXPA02006504A; KR20020073495A; BR9917604A; JP2003519218A; DE69912652D1; CZ20022627A3; PL198803B1; NO20023150D0; UA73336C2; PL355531A1; EA004055B1; ES2207312T3; EA200200728A1

Abstract

The invention provides a new and improved method for the preparation of 5-cyano-phtalid, which is a key intermediate in the preparation of the antidepressant compound citalopram.

Description

Process for the preparation of citalopram

The present invention relates to a process for the preparation of the main intermediate in the preparation of the well-known antidepressant drug citalopram, 1- [3- (dimethylamino) propyl ] -1- (4-fluorophenyl) -1, 3-dihydro-5-isobenzofurancarbonitrile.

Background

Citalopram is a well-known antidepressant drug which has been commercially available for many years and has the following structure:

formula I

It is a selective, centrally acting 5-hydroxytryptamine (5-hydroxytryptamine; 5-HT) reuptake inhibitor, and thus has antidepressant effect. The antidepressant action of this compound has been described in several publications, such as J.Hyttel, prog.neuro-Psychopharmacol. & biol.Psychiat., 1982, 6, 277-295 and A.Gravem, acta.Psychiatr.Scand., 1987, 75, 478-486. It has further been disclosed in EP-A474580 that the compounds exhibit therapeutic effects on dementia and cerebrovascular disorders.

Citalopram may be prepared by several published methods, one method and one intermediate for the preparation of citalopram is described in us patent 4650884. Commercial processes are disclosed in international patent applications WO 98019511, WO 98019512 and WO 98019513.

As regards the above process for the preparation of citalopram, the process comprising exchange of the 5-bromo group with cyano groups has proved to be less convenient on a commercial scale, due to the rather low yields, the impure products and, in particular, due to the difficulty in isolating the resulting citalopram from the corresponding 5-bromo compound.

It has now been found that in a new process for the preparation of citalopram, the main intermediate, wherein a halogen or a halogen of the general formula CF is located in the 5-position of 3-H-isobenzofuran-1-one, is obtained as a very pure product in high yield by a new catalytic process₃- (CF₂)_n-SO₂-wherein n is any suitable integer between 0 and 4 is exchanged with a cyanide group. Due to the correct cyanide substitution obtained at an early stage of the citalopram synthesis, a large work-up of the old cyanide exchange process of the previously described processes is avoided. The intermediates in the process are now easy to purify and are readily available in very high yields. Thereafter the main intermediate is subjected to a two-step sequential grignard reaction with 4-fluorophenyl magnesium halide and N, N-dimethylaminopropyl magnesium halide, respectively, thereby obtaining citalopram.

The preparation methods of the primary intermediates of the invention are described earlier in j.chem.soc., 1931, 867 and Tiroflet, j.in ball.soc.sci.betagne, 26, 35, 1951; the process for the preparation of this compound is a three-step synthesis starting from 5-nitro-benzofuranone with low yields, especially in the last step of the synthesis.

Summary of The Invention

Accordingly, the present invention relates to a novel process for the preparation of an intermediate in the preparation of citalopram comprising the reaction of a compound of formula IV with a cyanide source in the presence or absence of a catalyst:

formula IV

Wherein R' is Cl, Br, I or formula CF₃-(CF₂)_n-SO₂-wherein n is 1 to 4, thereby obtaining 5-cyano-isobenzofuran-1-one. This intermediate product may be further reacted to citalopram as described above.

The reaction of formula IV to 5-cyanobenzofuranone can be carried out in a number of conventional solvents, at low temperatures and with a slight excess of CN-. The environmental advantage of this process is that it uses only small amounts of heavy metals.

The cyanide source may conveniently be selected from cyanide sources such as (R "₄N) CN, wherein each R' represents C_1-8Alkyl, optionally two R "together with the nitrogen atom form a ring structure; NaCN, KCN, Zn (CN)₂Or Cu (CN).

The reaction of the present invention is carried out in the presence or absence of a catalyst. The catalyst is a Ni (O), Pd (O) or Pd (II) catalyst as described by Sakakibara et al, Bull. chem. Soc. Jpn., 61, 1985-1990, (1988), with the preferred catalyst being Ni (PPh)₃)₃Or Pd (PPh)₃)₄Or Pd (dba)₃Or Pd (PPh)₂Cl₂。

In a particularly preferred embodiment, the nickel (O) complex is prepared in situ prior to the cyanide exchange reaction by reacting a nickel (II) precursor such as NiCl with a metal such as zinc, magnesium or manganese in the presence of an excess of a complex ligand, preferably triphenylphosphine₂Or NiBr₂And (4) reducing.

The amount of Pd or Ni catalyst used is generally in the range of from 0.5 to 10, preferably 2 to 6, most preferably about 4 to 5 mole%.

Cu⁺And Zn²⁺Can be added to the reaction mixture in sub-stoichiometric amounts and can act as a recyclable cyanide source that accepts cyanide from other cyanide sources such as NaCN or KCN. Cu⁺And Zn²⁺The substoichiometric amounts of (b) mean 1 to 20%, preferably 5 to 10%, respectively.

The reaction may be carried out in any conventional solvent, as described by Sakakibara et al in Bull. chem. Soc. Jpn., 61, 1985-assault 1990, (1988). Preferred solvents are acetonitrile, ethyl acetate, THF, DMF or NMP.

In one aspect of the invention, a compound of formula IV (wherein R is Cl) is reacted with NaCN in Ni (PPh)₃)₃In the presence of Ni (PPh)₃)₃Preferably prepared in situ as described above.

In another aspect of the invention, a compound of formula IV (wherein R is Br or I) is reacted with KCN, NaCN, CuCN or Zn (CN)₂In Pd (PPh)₃)₄In the presence of (a). In a particular aspect of the invention, Cu (CN) and Zn (CN)₂Added in substoichiometric amounts as recyclable cyanide source.

In another aspect of the invention, cu (cn) is a cyanide source and no catalyst.

In a preferred embodiment of the invention, the reaction is carried out at elevated temperature.

In a particular aspect of the invention, the reaction is carried out as a neat reaction, i.e., without the addition of a solvent.

In another aspect of the invention, the reaction is carried out in a reaction of the general formula R₄N⁺X^-Wherein R is an alkyl group, or two R groups together form a ring, and X^-Is a counter ion. In one embodiment of the invention, R₄N⁺X^-Represents:

in another particular aspect of the invention, the reaction is carried out in a non-polar solvent such as benzene, xylene or 1, 3, 5-trimethylbenzene and under the influence of microwaves, for example using a Synthewave1000^TM(Prolabo Co.). In a particular aspect of the invention, the reaction is carried out without the addition of a solvent.

The temperature range depends on the type of reaction, and if no catalyst is present, the preferred temperature range is 100-200 ℃. However, when the reaction is carried out under the influence of microwaves, the temperature in the reaction mixture can be raised above 300 ℃. The more preferred temperature range is 120-170 ℃. The most preferred range is 130-150 ℃.

If a catalyst is present, the preferred temperature range is between 0 and 100 ℃. More preferably, the temperature is in the range of 40 to 90 ℃. The most preferred temperature range is 60-90 ℃.

Other reaction conditions, solvents, etc., are conventional for such reactions and can be readily determined by one skilled in the art.

Examples

The invention is further illustrated by the following examples.

Experiment of

Example 1

Zn(CN)₂A mixture of (2.4g, 0.02mol) and 5-bromo-3H-isobenzofuran-1-one (4.2g, 0.02mol) in DMF (80ml) was stirred at room temperature under argon atmosphere for 30 minutes, then dissolved oxygen was removed by bubbling argon into the reaction mixture for 10 minutes before adding tetrakis (triphenylphosphine) palladium (0) (1.2g, 0.00096 mol). The reaction was then heated at 75 ℃ for 3 hours, then the solvent was removed under reduced pressure and the residue poured into water (150 ml). Filtration and vacuum drying gave crude 5-cyano-3H-isobenzofuran-1-one (2.8g) (HPLC 95%). The analytical sample was obtained by recrystallization from acetic acid.

Example 2

Zn(CN)₂A mixture of (0.3g, 0.00256mol), NaCN (1g, 0.02mol) and 5-bromo-3H-isobenzofuran-1-one (4.2g, 0.02mol) in DMF (80ml) was stirred at room temperature under argonAfter 30 minutes, dissolved oxygen was removed by bubbling argon into the reaction mixture for 10 minutes before adding tetrakis (triphenylphosphine) palladium (O) (1.2g, 0.00096 mol). The reaction was then heated at 75 ℃ for 3 hours, then the solvent was removed under reduced pressure and the residue poured into water (150 ml). Filtration and vacuum drying gave crude 5-cyano-3H-isobenzofuran-1-one (2.7g) (HPLC 94%). The analytical sample was obtained by recrystallization from acetic acid.

Example 3

5-bromo-3H-isobenzofuran-1-one (4.2g, 0.02mol) and Cu (CN)₂A mixture of (2.3g, 0.02mol) in NMP (60ml) was stirred at 140 ℃ for 3 hours. The solvent was then distilled off under reduced pressure, and the residue was refluxed in water (150ml) for 10 minutes and then allowed to cool to room temperature. Filtration and vacuum drying gave crude 5-cyano-3H-isobenzofuran-1-one (2.1g) (HPLC 97%). The analytical sample was obtained by recrystallization from acetic acid.

Example 4

Zn(CN)₂A mixture of (2.4g, 0.02mol) and 5-iodo-3H-isobenzofuran-1-one (5.24g, 0.02mol) in DMF (80ml) was stirred at room temperature under argon atmosphere for 30 minutes, then dissolved oxygen was removed by bubbling argon into the reaction mixture for 10 minutes before adding tetrakis (triphenylphosphine) palladium (O) (1.2g, 0.00096 mol). The reaction was then heated at 75 ℃ for 3 hours, then the solvent was removed under reduced pressure and the residue poured into water (150 ml). Filtration and vacuum drying gave crude 5-cyano-3H-isobenzofuran-1-one (2.4g) (HPLC 93%). The analytical sample was obtained by recrystallization from acetic acid.

Example 5

NiCl under nitrogen atmosphere₂A mixture of (0.2g, 0.0015mol) and triphenylphosphine (1.6g, 0.0061mol) in acetonitrile (80ml) was heated at reflux for 45 minutes, and after cooling to room temperature, zinc powder (0.39g, 0.006mol) was added, stirring was carried out for 15 minutes, followed by addition of a solution of 5-chloro-3H-isobenzofuran-1-one (3.4g, 0.02mol) in THF (40 ml). After stirring for a further 10 minutes, NaCN (1.1g, 0.021mol) was added and the reaction was heated at 70 ℃ for 3 hours, cooled, diluted with acetonitrile (50ml) and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was refluxed in water (150ml) for 10 minutes, and then allowed to cool to room temperature. Filtration and vacuum drying gave crude 5-cyano-3H-isobenzofuran-1-one (2.5 g). The analytical sample was obtained by recrystallization from acetic acid.

Claims

1. A process for preparing a compound of the formula:

comprising reacting isobenzofuran-1-one of the formula with a cyanide source, optionally in the presence of a catalyst,

wherein R' representsTable one halogen, wherein the catalyst is selected from the group consisting of Ni (PPh)₃)₃、Pd(PPh₃)₄、Pd(dba)₃Or Pd (PPh)₂Cl₂。

2. The process of claim 1 wherein the starting material is an isobenzofuran-1-one with a Cl, Br or I in the 5-position.

3. The process of claim 2 wherein the cyanide source is selected from the group consisting of KCN, NaCN, Zn (CN)₂Or CuCN, or a combination thereof.

4. The method of any one of claims 1 to 3, wherein Zn²⁺Or Cu⁺Combined with another cyanide source in a substoichiometric amount.

5. The process of any of claims 1-3, wherein 5-chloro-isobenzofuran-1-one is reacted with NaCN in the presence of a nickel catalyst.

6. The process of claim 5 wherein the nickel catalyst is prepared by reacting NiCl₂With a reducing agent in PPh₃In situ prepared by reaction in the presence of (PPh)₃)₃。

7. A process according to any one of claims 1 to 3, wherein the 5-bromo or 5-iodo-isobenzofuran-1-one is in Pd (PPh)₃)₄With KCN, NaCN, Zn (CN)₂Or CuCN or a combination thereof.

8. A process according to any one of claims 1 to 3, wherein 5-bromo or 5-iodo-isobenzofuran-1-one is reacted with KCN, NaCN, Zn (CN)₂Or CuCN or a combination thereof, and the process is carried out without a catalyst.

9. The method of claim 8, wherein the reaction is carried out as a net reaction.

10. The method of claim 6, wherein the reducing agent is zinc.